Gene expression and ultra-structural evidence for metabolic derangement in the primary mitral regurgitation heart.

Aims: Chronic neurohormonal activation and haemodynamic load cause derangement in the utilization of the myocardial substrate. In this study, we test the hypothesis that the primary mitral regurgitation (PMR) heart shows an altered metabolic gene profile and cardiac ultra-structure consistent with decreased fatty acid and glucose metabolism despite a left ventricular ejection fraction (LVEF) > 60%. Methods and results: Metabolic gene expression in right atrial (RA), left atrial (LA), and left ventricular (LV) biopsies from donor hearts (n = 10) and from patients with moderate-to-severe PMR (n = 11) at surgery showed decreased mRNA glucose transporter type 4 (GLUT4), GLUT1, and insulin receptor substrate 2 and increased mRNA hexokinase 2, O-linked N-acetylglucosamine transferase, and O-linked N-acetylglucosaminyl transferase, rate-limiting steps in the hexosamine biosynthetic pathway. Pericardial fluid levels of neuropeptide Y were four-fold higher than simultaneous plasma, indicative of increased sympathetic drive. Quantitative transmission electron microscopy showed glycogen accumulation, glycophagy, increased lipid droplets (LDs), and mitochondrial cristae lysis. These findings are associated with increased mRNA for glycogen synthase kinase 3ß, decreased carnitine palmitoyl transferase 2, and fatty acid synthase in PMR vs. normals. Cardiac magnetic resonance and positron emission tomography for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake showed decreased LV [18F]FDG uptake and increased plasma haemoglobin A1C, free fatty acids, and mitochondrial damage-associated molecular patterns in a separate cohort of patients with stable moderate PMR with an LVEF > 60% (n = 8) vs. normal controls (n = 8). Conclusion: The PMR heart has a global ultra-structural and metabolic gene expression pattern of decreased glucose uptake along with increased glycogen and LDs. Further studies must determine whether this presentation is an adaptation or maladaptation in the PMR heart in the clinical evaluation of PMR.

The origin, evolution, and molecular diversity of the chemokine system.

Chemokine signalling performs key functions in cell migration via chemoattraction, such as attracting leukocytes to the site of infection during host defence. The system consists of a ligand, the chemokine, usually secreted outside the cell, and a chemokine receptor on the surface of a target cell that recognises the ligand. Several noncanonical components interact with the system. These include a variety of molecules that usually share some degree of sequence similarity with canonical components and, in some cases, are known to bind to canonical components and/or to modulate cell migration. Whereas canonical components have been described in vertebrate lineages, the distribution of the noncanonical components is less clear. Uncertainty over the relationships between canonical and noncanonical components hampers our understanding of the evolution of the system. We used phylogenetic methods, including gene-tree to species-tree reconciliation, to untangle the relationships between canonical and noncanonical components, identify gene duplication events, and clarify the origin of the system. We found that unrelated ligand groups independently evolved chemokine-like functions. We found noncanonical ligands outside vertebrates, such as TAFA "chemokines" found in urochordates. In contrast, all receptor groups are vertebrate-specific and all-except ACKR1-originated from a common ancestor in early vertebrates. Both ligand and receptor copy numbers expanded through gene duplication events at the base of jawed vertebrates, with subsequent waves of innovation occurring in bony fish and mammals.

A Retrospective Evaluation of Endo-Aortic Balloon Occlusion Compared to External Clamping in Minimally Invasive Mitral Valve Surgery.

We compare outcomes of endo-aortic balloon occlusion (EABO) vs external aortic clamping (EAC) in patients undergoing minimally invasive mitral valve surgery (MIMVS) in the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database. Adults undergoing mitral valve surgery (July 2017-December 2018) were identified within the STS database (N = 60,607). Total 7,978 patients underwent a minimally invasive approach (including robotically assisted). About 1,163 EABO patients were 1:1 propensity-matched to EAC patients using exact matching on age, sex, and type of mitral procedure, and propensity score average matching for 16 other risk indicators. Early outcomes were compared. Categorical variables were compared using logistic regression; hospital and intensive care unit length of stay were compared using negative binomial regression. In the matched cohort, mean age was 62 years; 35.9% were female, and 86% underwent mitral valve repair. Cardiopulmonary bypass time was shorter for EABO vs EAC group (125.0 ± 53.0 vs 134.0 ± 67.0 minutes, P = 0.0009). There was one aortic dissection in the EAC group and none in the EABO group (P value > 0.31), and no statistically significant differences in cross-clamp time, major intraoperative bleeding, perioperative mortality, stroke, new onset of atrial fibrillation, postoperative acute kidney injury, success of repair. Median hospital LOS was shorter for EABO vs EAC procedures (4 vs 5 days, P < 0.0001). In this large, retrospective, STS database propensity-matched analysis ofpatients undergoing MIMVS, we observed similar safety outcomes for EABO and EAC, including no aortic dissections in the EABO group. The EABO group showed slightly shorter CPB times and hospital LOS.

Shallow Whole-Genome Sequencing of Aedes japonicus and Aedes koreicus from Italy and an Updated Picture of Their Evolution Based on Mitogenomics and Barcoding.

Aedes japonicus and Aedes koreicus are two invasive mosquitoes native to East Asia that are quickly establishing in temperate regions of Europe. Both species are vectors of arboviruses, but we currently lack a clear understanding of their evolution. Here, we present new short-read, shallow genome sequencing of A. japonicus and A. koreicus individuals from northern Italy, which we used for downstream phylogenetic and barcode analyses. We explored associated microbial DNA and found high occurrences of Delftia bacteria in both samples, but neither Asaia nor Wolbachia. We then assembled complete mitogenomes and used these data to infer divergence times estimating the split of A. japonicus from A. koreicus in the Oligocene, which was more recent than that previously reported using mitochondrial markers. We recover a younger age for most other nodes within Aedini and other Culicidae. COI barcoding and phylogenetic analyses indicate that A. japonicus yaeyamensis, A. japonicus amamiensis, and the two A. koreicus sampled from Europe should be considered as separate species within a monophyletic species complex. Our studies further clarify the evolution of A. japonicus and A. koreicus, and indicate the need to obtain whole-genome data from putative species in order to disentangle their complex patterns of evolution.

Elevated cardiac hemoglobin expression is associated with a pro-oxidative and inflammatory environment in primary mitral regurgitation.

BACKGROUND: Primary mitral regurgitation (PMR) is associated with oxidative and inflammatory myocardial damage. We reported greater exosome hemoglobin (Hb) in pericardial fluid (PCF) versus plasma, suggesting a cardiac source of Hb. OBJECTIVE: Test the hypothesis that Hb is produced in the PMR heart and is associated with increased inflammation. METHODS AND RESULTS: Hb gene expression for subunits alpha (HBA) and beta (HBB) was assessed in right atria (RA), left atria (LA) and left ventricular (LV) tissue from donor hearts (n = 10) and PMR patient biopsies at surgery (n = 11). PMR patients (n = 22) had PCF and blood collected for macrophage markers, pro-inflammatory cytokines, and matrix metalloproteinases (MMPs). In-situ hybridization for HBA mRNA and immunohistochemistry for Hb-alpha (Hbα) and Hb-beta (Hbß) protein was performed on PMR tissue. RESULTS: HBA and HBB genes are significantly increased (>4-fold) in RA, LA, and LV in PMR vs. normal hearts. In PMR tissue, HBA mRNA is expressed in both LV cardiomyocytes and interstitial cells by in-situ hybridization; however, Hbα and Hbß protein is only expressed in interstitial cells by immunohistochemistry. PCF oxyHb is significantly increased over plasma along with low ratios (<1.0) of haptoglobin:oxyHb and hemopexin:heme supporting a highly oxidative environment. Macrophage chemotactic protein-1, tumor necrosis factor-α, interleukin-6, and MMPs are significantly higher in PCF vs. plasma. CONCLUSION: There is increased Hb production in the PMR heart coupled with the inflammatory state of the heart, suggests a myocardial vulnerability of further Hb delivery and/or production during cardiac surgery that could adversely affect LV functional recovery.

Cost and Clinical Outcomes Evaluation Between the Endoaortic Balloon and External Aortic Clamp in Cardiac Surgery.

OBJECTIVE: Endoaortic balloon occlusion facilitates cardioplegic arrest during minimally invasive surgery (MIS). Studies have shown endoclamping to be as safe as traditional aortic clamping. We compared outcomes and hospital costs of endoclamping versus external aortic occlusion in a large administrative database. METHODS: There were 52,882 adults undergoing eligible cardiac surgery (October 2015 to March 2020) identified in the Premier Healthcare Database. Endoclamp procedures (n = 419) were 1:3 propensity score matched to similar procedures using external aortic occlusion (n = 1,244). Generalized linear modeling measured differences in in-hospital complications (major adverse renal and cardiac events, including mortality, new-onset atrial fibrillation, acute kidney injury [AKI], myocardial infarction [MI], postcardiotomy syndrome, stroke/transient ischemic attack [TIA], and aortic dissection) and length of stay (LOS). RESULTS: The mean age was 63 years, and 53% were male (n = 882). The majority (93%, n = 1,543) were mitral valve procedures, and 17% of procedures (n = 285) were robot-assisted. Total hospitalization costs were not statistically significantly different between the 2 groups ($52,158 vs $49,839, P = 0.06). The median LOS was significantly shorter in the endoclamp group (incident rate ratio = 0.87, P < 0.001). Mortality, atrial fibrillation, AKI, and stroke/TIA were similar between the 2 groups. MI and postcardiotomy syndrome were lower in the endoclamp group (odds ratio [OR] = 0.14, P = 0.006, and OR = 0.27, P = 0.005). There were no aortic dissections in the endoclamp group. CONCLUSIONS: Aortic endoclamping in MIS was associated with similar costs, shorter LOS, no dissections, and comparably low mortality and stroke rates when compared with external clamping in this hospital billing dataset. These results demonstrate the clinical safety and efficacy of endoaortic balloon clamping in a real-world setting. Further studies are warranted.

Metabolic decline in an insect ear: correlative or causative for age-related auditory decline?

One leading hypothesis for why we lose our hearing as we age is a decrease in ear metabolism. However, direct measurements of metabolism across a lifespan in any auditory system are lacking. Even if metabolism does decrease with age, a question remains: is a metabolic decrease a cause of age-related auditory decline or simply correlative? We use an insect, the desert locust Schistocerca gregaria, as a physiologically versatile model to understand how cellular metabolism correlates with age and impacts on age-related auditory decline. We found that auditory organ metabolism decreases with age as measured fluorometrically. Next, we measured the individual auditory organ's metabolic rate and its sound-evoked nerve activity and found no correlation. We found no age-related change in auditory nerve activity, using hook electrode recordings, and in the electrophysiological properties of auditory neurons, using patch-clamp electrophysiology, but transduction channel activity decreased. To further test for a causative role of the metabolic rate in auditory decline, we manipulated metabolism of the auditory organ through diet and cold-rearing but found no difference in sound-evoked nerve activity. We found that although metabolism correlates with age-related auditory decline, it is not causative. Finally, we performed RNA-Seq on the auditory organs of young and old locusts, and whilst we found enrichment for Gene Ontology terms associated with metabolism, we also found enrichment for a number of additional aging GO terms. We hypothesize that age-related hearing loss is dominated by accumulative damage in multiple cell types and multiple processes which outweighs its metabolic decline.

Rescue of False Lumen Frozen Elephant Trunk Deployment Intraoperatively.

Endovascular devices have become increasingly available, which has led to an increase in use of frozen elephant trunk stents for extended repair during type A aortic dissection. Frozen elephant trunk deployment is usually done under direct visualization of both the true and false lumen but rarely, the endograft can inadvertently end in the false lumen. This can lead to false lumen pressurization and end-organ malperfusion. Herein we describe a novel intraoperative rescue technique for misplaced frozen elephant trunk into the false lumen, easily executed in a standard operating room using transesophageal echocardiography and intravascular ultrasound guidance.

Plasma Exosome Hemoglobin Released During Surgery Is Associated With Cardiac Injury in Animal Model.

BACKGROUND: Patients with valvular heart disease require cardiopulmonary bypass and cardiac arrest. Here, we test the hypothesis that exosomal hemoglobin formed during cardiopulmonary bypass mediates acute cardiac injury in humans and in an animal model system. METHODS: Plasma exosomes were collected from arterial blood at baseline and 30 minutes after aortic cross-clamp release in 20 patients with primary mitral regurgitation and 7 with aortic stenosis. These exosomes were injected into Sprague-Dawley rats and studied at multiple times up to 30 days. Tissue was examined by hematoxylin and eosin stain, immunohistochemistry, transmission electron microscopy, and brain natriuretic peptide. RESULTS: Troponin I levels increased from 36 ± 88 ng/L to 3622 ± 3054 ng/L and correlated with exosome hemoglobin content (Spearman r = 0.7136, < .0001, n = 24). Injection of exosomes isolated 30 minutes after cross-clamp release into Sprague-Dawley rats resulted in cardiomyocyte myofibrillar loss at 3 days. Transmission electron microscopy demonstrated accumulation of electron dense particles of ferritin within cardiomyocytes, in the interstitial space, and within exosomes. At 21 days after injection, there was myofibrillar and myosin breakdown, interstitial fibrosis, elevated brain natriuretic peptide, and left ventricle diastolic dysfunction measured by echocardiography/Doppler. Pericardial fluid exosomal hemoglobin content is fourfold higher than simultaneous plasma exosome hemoglobin, suggesting a cardiac source of exosomal hemoglobin. CONCLUSIONS: Red blood cell and cardiac-derived exosomal hemoglobin may be involved in myocardial injury during cardiopulmonary bypass in patients with valvular heart disease.

Robotic Redo Mitral Valve Replacement and Atrioventricular Groove Pseudoaneurysm Repair.

We report the use of robot-assisted right thoracotomy in the management of a patient who presented with acute-on-chronic congestive heart failure, associated with a contained atrioventricular dissection and 2 prior mitral valve replacements. Our patient had evidence of a contained rupture, as represented by preoperative cross-sectional imaging. The anatomic sequela from this was a ventricular pseudoaneurysm, which was likely survivable due to adhesions from prior operations buttressing the margins of the defect. Expansion of the pseudoaneurysm likely contributed to the dehiscence of the prosthesis. Our case illustrates an unprecedented resolution of a serious complication, managed effectively and efficiently by a robot-assisted procedure. With a successful outcome of totally endoscopic and robot-assisted repair, we demonstrate the versatility of minimally invasive techniques in addressing complicated anatomy as well as a surgical field scarred by multiple prior surgeries.

Interstitial Collagen Loss, Myocardial Remodeling, and Function in Primary Mitral Regurgitation.

Interstitial collagen loss and cardiomyocyte ultrastructural damage accounts for left ventricular (LV) sphericity and decrease in LV twist and circumferential strain. Normal LV diastolic function belies significantly abnormal left atrial (LA) function and early LV diastolic untwist rate. This underscores the complex interplay of LV and LA myocardial remodeling and function in the pathophysiology of primary mitral regurgitation. In this study, we connect LA function with LV systolic and diastolic myocardial remodeling and function using cardiac magnetic resonance tissue tagging in primary mitral regurgitation.

Left Anterior Thoracotomy Minimally Invasive Aortic Valve Replacement Following Left Pneumonectomy.

We report the case of a 59-year-old man referred for aortic valve replacement for severe, symptomatic aortic insufficiency who underwent a minimally invasive left anterior thoracotomy aortic valve replacement. This approach was facilitated by his history of a left pneumonectomy for lung cancer 7 years prior to presentation, which resulted in a significant left mediastinal shift. The cannulation strategy and exposure were analogous to what would be expected from a standard right anterior thoracotomy minimally invasive aortic valve replacement. The minimally invasive approach allowed for early extubation and mobilization in a patient with moderate baseline pulmonary dysfunction.

Reduced Left Atrial Emptying Fraction and Chymase Activation in Pathophysiology of Primary Mitral Regurgitation.

Increasing left atrial (LA) size predicts outcomes in patients with isolated mitral regurgitation (MR). Chymase is plentiful in the human heart and affects extracellular matrix remodeling. Chymase activation correlates to LA fibrosis, LA enlargement, and a decreased total LA emptying fraction in addition to having a potential intracellular role in mediating myofibrillar breakdown in LA myocytes. Because of the unreliability of the left ventricular ejection fraction in predicting outcomes in MR, LA size and the total LA emptying fraction may be more suitable indicators for timing of surgical intervention.

Robotic mitral valve repair in a type B hemophiliac.

Hemophilia B is a rare X-linked recessive disorder that places surgical patients at an increased risk of bleeding. Patients with hemophilia are now achieving near-normal life expectancies and therefore the number of these patients requiring cardiac surgery due to the development of age-related cardiovascular disease may increase. We present the case of a young male with hemophilia B who was diagnosed with severe symptomatic mitral regurgitation and underwent successful robotic mitral valve repair. To our knowledge, this is the first report of a patient with hemophilia B who underwent robotic mitral valve repair.

Total Endovascular Arch Repair Using Needle Fenestration and Extracorporeal Membrane Oxygenation.

There remains a clinical need for endovascular repair of the ascending aorta and the aortic arch in patients who are prohibitively high risk for open surgical repair. Herein we present a case of a total endovascular arch repair by means of a novel technique for graft fenestration using a trans-septal needle with extracorporeal membrane oxygenation support. Although the use of trans-septal needle fenestration use has been described, the use in arch fenestrations has not. We present this case as an example of techniques that may be useful in the expanding landscape of endovascular ascending and arch repair.

Contemporary suprasternal transcatheter aortic valve replacement: A multicenter experience using a simple, reliable alternative access approach.

OBJECTIVES: To describe outcomes after suprasternal (SS) transcatheter aortic valve replacement (TAVR) as a new alternative access approach. BACKGROUND: There still remains a cohort of the TAVR population who are not suitable for a transfemoral (TF) approach. SS-TAVR is a safe and effective alternative to TF-TAVR and has now become our preferred alternative access route. METHODS: We retrospectively reviewed all patients from New York Presbyterian Hospital, Columbia University Medical Center and Princeton Baptist Medical Center who underwent SS-TAVR from 2015 to July 2018. A total of 84 patients were included in the study. RESULTS: Technical success was achieved in all cases. Thirty-day survival was 98.8% (n = 83). There were minimal complications. Most notably, there were no transient ischemic attacks or strokes (0%, n = 0). Reexploration for bleeding was 3.6% (n = 3), and major bleeding was 1.7% (n = 1). We also achieved satisfactory results with a mean aortic valve gradient of 6.07 ± 3.79 mmHg and an aortic valve area of 2.21 ± 0.51 cm2 . No patients had anything more than mild paravalvular leak. The mean length of stay (LOS) in the intensive care unit was 1.42 ± 1.23 days, and hospital LOS was 4.20 ± 3.29 days. CONCLUSIONS: SS access for TAVR is an extremely important technique to have in any valve team's alternative access armamentarium. This technique can be safely and reliably reproduced with any standard hybrid operating room setup and no additional equipment, and it can be used with any commercially available valve system. In the current experience, minimal complications and excellent early term results were obtained.

Draft Genome Sequences of Two Isolates of the Yeast Kazachstania servazzii Recovered from Soil in Ireland.

We sequenced two isolates of Kazachstania servazzii, UCD13 and UCD335, from soil in Ireland. Heterozygosity in these diploid genomes differs 19-fold between the two strains. Most currently available K. servazzii genome sequences come from Korean kimchi isolates, so our data will facilitate analysis of diversity in this species.

Suprasternal and Left Axillary Transcatheter Aortic Valve Replacement in Morbidly Obese Patients.

In morbidly obese patients who cannot undergo transfemoral, transaortic, or transapical transcatheter aortic valve replacement (TAVR) due to body habitus, suprasternal (SS) and left subclavian/axillary artery (LSCLA) approaches may provide safe TAVR access. Nine morbidly obese patients with a body mass index of 35 or more underwent SS-TAVR (7 patients) or LSCLA-TAVR (2 patients) at two institutions from 2015 to 2017. Mean age was 69.4 ± 7.3 years, and mean body mass index was 50.3 ± 10.6. There were no deaths, valve reinterventions, or reoperations. Three patients required new pacemakers. In morbidly obese patients who are not candidates for the other approaches, SS-TAVR and LSCLA-TAVR allow easier vascular access and prevent the need for thoracotomy or sternotomy.